Transforming growth factor-beta ligand traps for the treatment of disease

Abstract

The present application relates to methods using Transforming Growth Factor-β (TGF-β) ligand traps. The TGF-β ligand traps described herein may be suitable for combination therapy with an immunotherapy, for treating a disease or disorder such as a cancer. The TGF-β ligand traps described herein may also be suitable for monotherapy for treating a disease or disorder such as a cancer. In particular, provided herein are methods and compositions for treating a disease or disorder such as a cancer by administering a TGF-β ligand trap in combination with an immune checkpoint inhibitor.

1 . A method of treating cancer in a subject in need thereof, wherein the method comprises administering a nivolumab treatment and a treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5; wherein 
 (i) the nivolumab treatment comprises administering about 360-480 mg of nivolumab to the subject on about day 1 of a dosing cycle; and   (ii) the treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 comprises administering a dose of about 400-1600 mg of the polypeptide to the subject on about day 1 of the dosing cycle.   
     
     
         2 . The method of  claim 1 , wherein the nivolumab treatment comprises administering about 360 mg of nivolumab to the subject. 
     
     
         3 . The method of  claim 1  , wherein the nivolumab treatment comprises administering nivolumab to the subject a single time per dosing cycle. 
     
     
         4 . The method of  claim 1 , wherein the treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 comprises administering the polypeptide to the subject a single time per dosing cycle. 
     
     
         5 . The method of  claim 1 , wherein the dosing cycle begins on day 1 and ends on day 21. 
     
     
         6 . The method of any one of  claims 1-5 , wherein the dosing cycle is repeated about 10 to about 20 times, about 15 to about 25 times, about 20 to about 30 times, about 25 to about 35 times, or about 30 to about 40 times. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A method of treating cancer in a subject in need thereof, wherein the method comprises administering a nivolumab treatment and a treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO: 1 to 5; wherein 
 (i) the nivolumab treatment comprises administering about 360-480 mg of nivolumab to the subject on about day 1 of a dosing cycle; and   (ii) the treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO: 1 to 5 comprises administering a dose of about 400-1600 mg of the polypeptide to the subject on about day 1 of the dosing cycle and a dose of about 400-1600 mg of the polypeptide on about day 15 of the dosing cycle.   
     
     
         13 . The method of  claim 12 , wherein the dose of the polypeptide that is administered on about day 1 and the dose of the polypeptide that is administered on about day 15 are the same. 
     
     
         14 . The method of  claim 12  , wherein the nivolumab treatment comprises administering about 480 mg of nivolumab to the subject. 
     
     
         15 . The method of  claim 12 , wherein the nivolumab treatment consists of administering nivolumab to the subject once per dosing cycle. 
     
     
         16 . The method of  claim 12 , wherein the treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO: 1 to 5 consists of administering the polypeptide to the subject twice per dosing cycle. 
     
     
         17 . The method of  claim 12 , wherein the dosing cycle begins on day 1 and ends on day 28. 
     
     
         18 . The method of any one of  claims 12-17 , wherein the dosing cycle is repeated about 10 to about 20 times, about 15 to about 25 times, about 20 to about 30 times, about 25 to about 35 times, or about 30 to about 40 times. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 12 , wherein the dosing cycle is repeated about 26 times. 
     
     
         24 . The method of  claim 1 , wherein the dose of the polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 is about 400 mg, about 800 mg, about 1200 mg, or about 1600 mg. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the nivolumab is present in a pharmaceutical composition that further comprises an excipient. 
     
     
         29 . The method of  claim 1 , wherein the polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 is present in a pharmaceutical composition that further comprises an excipient. 
     
     
         30 . The method of  claim 1 , wherein the nivolumab and the polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 are formulated together in a single pharmaceutical composition that further comprises an excipient. 
     
     
         31 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence consisting of SEQ ID 1. 
     
     
         32 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence consisting of SEQ ID 2. 
     
     
         33 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence consisting of SEQ ID 3. 
     
     
         34 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence consisting of SEQ ID 4. 
     
     
         35 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence consisting of SEQ ID 5. 
     
     
         36 . The method of  claim 1 , wherein the cancer comprises an advanced solid tumor. 
     
     
         37 . The method of  claim 1 , wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), microsatellite-stable colorectal carcinoma (MSS CRC) and pancreatic ductal adenocarcinoma (PDAC). 
     
     
         38 . The method of  claim 1 , wherein 
 (a) the method results in a reduction in the size of a tumor or in the number of tumors associated with the cancer; and/or   (b) the subject is resistant or refractory to or intolerant of existing standard cancer therapies known to provide clinical benefit; and/or   (c) the subject is resistant or refractory to immunotherapy that inhibits PD-1 signaling; and/or   (d) the subject is resistant or refractory to anti-PD-(L)1-based immunotherapy.   
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . A method of preventing or treating a cancer in a subject comprising administering to a subject in need thereof an effective amount of a TGF-β ligand trap and nivolumab. 
     
     
         43 . The method of  claim 42 , wherein the cancer is resistant or refractory to anti-PD1 based immunotherapy or anti-PD-L1-based immunotherapy. 
     
     
         44 . The method of  claim 43 , wherein the anti-PD-1 based immunotherapy comprises an anti-PD-1 antibody. 
     
     
         45 . The method of  claim 44 , wherein the anti-PD-1 antibody is nivolumab. 
     
     
         46 . The method of  claim 42 , wherein the nivolumab is present in a pharmaceutical composition that further comprises an excipient. 
     
     
         47 . The method of  claim 42 , wherein the TGF-β ligand trap is present in a pharmaceutical composition that further comprises an excipient. 
     
     
         48 . The method of  claim 42 , wherein the nivolumab and the TGF-β ligand trap are formulated together in a single pharmaceutical composition that further comprises an excipient. 
     
     
         49 . The method of  claim 42 , wherein the TGF-β ligand trap is a polypeptide comprising an amino acid sequence of any one of the sequences of SEQ ID Nos: 1 to 5. 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 42 , wherein the TGF-β ligand trap is AVID200. 
     
     
         56 . The method of  claim 42 , wherein the method comprises administering a therapeutically effective amount of the TGF-β ligand trap to the subj ect. 
     
     
         57 . The method of  claim 56 , wherein the therapeutically effective amount is about 400 mg to about 1600 mg of the TGF-β ligand trap to the subject. 
     
     
         58 . The method of  claim 57 , wherein the therapeutically effective amount comprises at least one dose selected from the group consisting of: about 400 mg, about 800 mg, about 1200 mg, and about 1600 mg. 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . The method of  claim 42 , wherein the method comprises administering the TGF-β ligand trap every two weeks (Q2W). 
     
     
         64 . The method of  claim 42 , wherein the method comprises administering the TGF-β ligand trap every three weeks (Q3W). 
     
     
         65 . The method of  claim 42 , wherein the TGF-β ligand trap is administered by intravenous infusion. 
     
     
         66 . The method of  claim 42 , wherein nivolumab is administered at a dose of 360 mg or 480 mg. 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 42 , wherein nivolumab is administered every three weeks Q3W or every four weeks (Q4W). 
     
     
         69 . (canceled) 
     
     
         70 . The method of  claim 42 , wherein nivolumab is administered by intravenous infusion. 
     
     
         71 . The method of  claim 42 , wherein the cancer is relapsed or refractory. 
     
     
         72 . The method of  claim 71 , wherein the cancer is relapsed or refractory to chemotherapy, radiation therapy, or immunotherapy. 
     
     
         73 . The method of  claim 72 , wherein the relapsed or refractory cancer is resistant to treatment with nivolumab. 
     
     
         74 . The method of  claim 42 , wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), colorectal cancer, squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), ovarian cancer, breast cancer, and pancreatic cancer. 
     
     
         75 . The method of  claim 42 , wherein the method results in a reduction in the size of a tumor or in the number of tumors associated with the cancer. 
     
     
         76 . The method of  claim 42 , wherein the method results in a reduction in an indicia of the presence or progression of the cancer. 
     
     
         77 . The method of  claim 1  further comprising administering at least one therapeutic agent. 
     
     
         78 . The method of  claim 77 , wherein the at least one therapeutic agent comprises a therapeutic antibody. 
     
     
         79 . The method of  claim 1 , wherein the cancer is associated with high levels of TGF-β. 
     
     
         80 . The method of  claim 1 , wherein the subject has:
 (a) elevated levels of a biomarker as compared to levels of the biomarker in a reference population; or   (b) decreased levels of a biomarker as compared to levels of the biomarker in a reference population; and 
 wherein the level of the biomarker is predictive of responsiveness to the nivolumab treatment and/or the treatment with the polypeptide. 
     
     
         81 . The method of  claim 80 , wherein 
 (a) the elevated levels of the biomarker are about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% greater than the levels of the biomarker in the reference population; or   (b) the elevated levels of the biomarker are equal to or about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% greater than the levels of the biomarker in the top 10%, top 5%, top 4%, top 3%, top 2%, or top 1% in the reference population; or   (c) the decreased levels of the biomarker are about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% less than the levels of the biomarker in the reference population; or   (d) the decreased levels of the biomarker are equal to or about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% less than the levels of the biomarker in the bottom 10%, bottom 5%, bottom 4%, bottom 3%, bottom 2%, or bottom 1% in the reference population.   
     
     
         82 . (canceled) 
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . The method of  claim 80 , wherein the level of the biomarker is determined by:
 (a) gene expression profiling for TGF-β epithelial-mesenchymal transition/cancer-associated fibroblasts (EMT/CAF), interferon gamma (IFNγ) signatures, cluster of differentiation 8 (CD8) tumor infiltrating lymphocytes (TIL), and/or T/NK cells;   (b) monitoring TGF-β signaling pathways;   (c) cytokine profiling in tumors and/or periphery;   (d) peptide or protein profiling in a tissue;   (e) profiling circulating micro ribonucleic acid;   (f) profiling circulating deoxyribonucleic acid (ctDNA);   (g) whole exome sequencing; and/or   (h) biomarker immunostaining.   
     
     
         86 . The method of  claim 80 , wherein the level of the biomarker is the protein level of the biomarker. 
     
     
         87 . The method of  claim 80 , wherein the level of the biomarker is the mRNA level of the biomarker. 
     
     
         88 . The method of  claim 87 , wherein the mRNA level is determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). 
     
     
         89 . The method of  claim 80 , wherein the level of the biomarker is in a tissue. 
     
     
         90 . The method of any one of  claim 80 , wherein the subject is a human. 
     
     
         91 . The method of any one of  claim 80 , wherein the biomarker is collagen. 
     
     
         92 . The method of any one of  claim 80 , wherein the biomarker is CD8 tumor infiltrating lymphocytes. 
     
     
         93 . The method of  claim 80 , wherein 
 (a) the reference population consists of 1, 5, 10, 25, 50, 75, 100, 200, 250, 300, 400, 500, or 1000 individuals; and/or   (b) the reference population consists of healthy people; and/or   (c) the reference population consists of people of the same age, weight, and/or gender as the subject; and/or   (d) the reference population consists of people without cancer.   
     
     
         94 . (canceled) 
     
     
         95 . (canceled) 
     
     
         96 . (canceled) 
     
     
         97 . The method of  claim 1 , wherein the method further comprises monitoring the level of the biomarker in the subject. 
     
     
         98 . A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO: 1 to 5 at a dose of about 400-1600 mg. 
     
     
         99 . The method of  claim 98 , wherein the method further comprises administering about 360 mg Q3W of nivolumab to the subject. 
     
     
         100 . The method of  claim 98 , wherein the method further comprises administering about 480 mg Q4W of nivolumab to the subject. 
     
     
         101 . The method of  claim 98 , wherein the treatment with a polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO: 1 to 5 comprises administering the polypeptide to the subject a single time per dosing cycle. 
     
     
         102 . The method of  claim 98 , wherein the dosing cycle begins on day 1 and ends on day 21. 
     
     
         103 . The method of  claim 98 , wherein the dosing cycle is repeated about 10 to about 20 times, about 15 to about 25 times, about 20 to about 30 times, about 25 to about 35 times, or about 30 to about 40 times. 
     
     
         104 . (canceled) 
     
     
         105 . (canceled) 
     
     
         106 . (canceled) 
     
     
         107 . (canceled) 
     
     
         108 . (canceled) 
     
     
         109 . The method of  claim 98 , wherein the dose of the polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 is about 400 mg, about 800 mg, about 1200 mg, or about 1600 mg. 
     
     
         110 . (canceled) 
     
     
         111 . (canceled) 
     
     
         112 . (canceled) 
     
     
         113 . The method of  claim 98 , wherein the polypeptide is administered Q3W or Q4W. 
     
     
         114 . (canceled) 
     
     
         115 . The method of  claim 98 , wherein the nivolumab and the polypeptide comprising an amino acid sequence selected from any one of SEQ ID NO:1 to 5 are formulated together in a single pharmaceutical composition that further comprises an excipient. 
     
     
         116 . (canceled) 
     
     
         117 . (canceled) 
     
     
         118 . (canceled) 
     
     
         119 . (canceled) 
     
     
         120 . (canceled) 
     
     
         121 . The method of  claim 98 , wherein the cancer comprises an advanced solid tumor. 
     
     
         122 . The method of  claim 98 , wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), microsatellite-stable colorectal carcinoma (MSS CRC), renal cell carcinoma (RCC), and pancreatic ductal adenocarcinoma (PDAC). 
     
     
         123 . The method of  claim 98 , wherein the method results in a reduction in the size of a tumor or in the number of tumors associated with the cancer. 
     
     
         124 . The method of  claim 98 , wherein 
 (a) the subject is resistant or refractory to or intolerant of existing standard cancer therapies known to provide clinical benefit; and/or   (b) the subject is resistant or refractory to immunotherapy that inhibits PD-1 signaling; and/or   (c) the subject is resistant or refractory to anti-PD-(L)1-based immunotherapy.   
     
     
         125 . (canceled) 
     
     
         126 . (canceled) 
     
     
         127 . (canceled) 
     
     
         128 . (canceled)